In presenting the dissertation as a partial fulfillment of the requirements for an advanced degree from the Georgia Institute of Technology, I agree that the Library of the Institute shall make it available for inspection and circulation in accordance with its regulations governing materials of this type. I agree that permission to copy from, or to publish from, this dissertation may be granted by the professor under whose direction it was written, or, in his absence, by the Dean of the Graduate Division when such copying or publication is solely for scholarly purposes and does not involve potential financial gain. It is under­ stood that any copying from, or publication of, this dis­ sertation which involves potential financial gain will not be allowed without written permission. 3/17/65 b THE MECHANISM OF THE NORMAL GRIGNARD ADDITION REACTION WITH KETONES AND NITRILES A THESIS Presented to The Faculty of the Graduate Division by Robert Charles Arnott In Partial Fulfillment of the Requirements for the Degree Master of Science in Chemistry Georgia Institute of Technology June, 1967 THE MECHANISM OF THE NORMAL GRIGNARD ADDITION REACTION WITH KETONES AND NITRIDES Approved: Chairman 77 i yO i ... i Date Approved by Chairman ii ACKNOWLEDGMENTS I wish to express my appreciation to Dr. Eugene C. Ashby who suggested the problem and whose encouragement and enthusiasm were a constant driving force. I also wish to convey my thanks to the other members of the reading committee, Dr. Leon H. Zalkow and Dr. Charles L. Liotta, for their helpful comments and criticisms during the preparation of this thesis. The Petroleum Research Fund of the American Chemical Society supported this work through Grant No. 2057-Al,3, and this financial assistance is appreciated. Financial assistance granted through a teaching assistantship by Georgia Institute of Technology is also greatly appreciated. iii TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ii LIST OF TABLES iv LIST OF ILLUSTRATIONS v SUMMARY vi Chapter I. INTRODUCTION AND HISTORICAL BACKGROUND 1 II. EXPERIMENTAL 20 Preparation of Methylmagnesium Iodide in Diethyl Ether Preparation of Magnesium Bromide in Diethyl Ether Preparation of Magnesium Iodide in Diethyl Ether Preparation of Dimethylmagnesium in Diethyl Ether Preparation of Methylmagnesium Chloride in Triethylamine Preparation of Phenylmagnesium Bromide in Diethyl Ether Preparation of Phenylmagnesium Bromide in Triethylamine Preparation of 1,1-Diphenylethanol Preparation of 9-Methyl-9-Fluorenol Preparation of Methylmagnesium 1,1-Diphenylethoxide in Diethyl Ether Reaction of Methylmagnesium 1,1-Diphenylethoxide with Magnesium Iodide Dietherate in Diethyl Ether Preparation of k,k'-Dimethoxybenzophenone Preparation of 2-Methyl-^'-mercaptomethylbenzophenone Preparation of l-(o-tolyl)-l-(methylmercaptophenyl)ethanol Reaction of Methylmagnesium Iodide with Benzonitrile in Diethyl Ether Reaction of Methylmagnesium Iodide with Benzophenone in Diethyl Ether Reaction of Phenylmagnesium Iodide with Benzophenone in Diethyl Ether Reaction of Phenylmagnesium Bromide with Benzophenone in Diethyl Ether Method of making a Kinetic Run and Subsequent Analysis III. DISCUSSION AND RESULTS ^0 IV. CONCLUSIONS AND RECOMMENDATIONS 53 LITERATURE CITED 55 iv LIST OF TABLES Table Page 1. Fractional Crystallization of Methylmagnesium Chloride from Triethylamine 25 2. Fractional Crystallization of Methylmagnesium 1,1-Diphenyl- ethoxide from Diethyl Ether (Method A) 30 3- Fractional Crystallization of Methylmagnesium 1,1-Diphenyl- ethoxide from Diethyl Ether (Method B) 30 k. Products from the Reaction of Methylmagnesium 1,1-Diphenyl- ethoxide with Magnesium Iodide Dietherate in Diethyl Ether 31 5» Products from the Reaction of Methylmagnesium Iodide with Benzonitrile in Diethyl Ether (using a O.^M solution of the Grignard compound) 3^- 6. Products from the Reaction of Methylmagnesium Iodide with Benzonitrile in Diethyl Ether (using a 1.0M solution of the Grignard compound) 35 7. Products from the Reaction of Methylmagnesium Iodide with Benzophenone (using normal addition and a 0.1M solution of the Grignard compound) 36 8. Products from the Reaction of Methylmagnesium Iodide with Benzophenone (using normal addition and a 1.0M solution of theGrignard compound) 37 9. Products from the Reaction of Methylmagnesium Iodide with Benzophenone (using inverse addition) 37 10. Products from the Reaction of Phenylmagnesium Bromide with Benzophenone 38 11. Ultraviolet Absorption Bands for Ketones k$ 12. Stability of 2-Methyl-^'-mercaptomethylbenzophenone in Triethylamine 50 13. Kinetic Data on the Reaction of 2-Methyl-h'-mercaptomethyl­ benzophenone with Methylmagnesium Chloride in Triethyl­ amine 52 V LIST OF ILLUSTRATIONS Figure Page 1. Graph of the Pseudo-first Order Rate Constant versus Concentration of the Grignard Compound from the Reaction of 2,^-Dimethyl-4'-mercaptomethylbenzophenone with Methylmagnesium Bromide in Diethyl Ether 18 SUMMARY The normal addition reaction of a ketone with a Grignard reagent, followed by hydrolysis of the reaction mixture results in the formation of a tertiary alcohol. The intermediates resulting from the reaction of benzophenone with methyl and phenyl Grignard compounds in 1:2 stoichio- metry have been isolated, prior to hydrolysis, by fractional crystalliza­ tion of the reaction mixtures. As the solvent was removed from the reaction mixture under vacuum, a precipitate resulted which was filtered in the dry box. Further stepwise removal of solvent from the reaction mixture resulted in several fractions. In all cases the first fractions obtained were found to contain an alkoxymagnesium halide. This was true regardless of which Grignard compound was used or whether the initial Grignard compound concentration was 0.1M or 1.0M in diethyl ether. The final fraction resulting from the removal of the last traces of solvent, was found to contain unreacted Grignard compound. Redistribution has been found to occur readily between methyl­ magnesium 1,1-diphenylethoxide and magnesium iodide dietherate in diethyl solution to form methylmagnesium iodide in 1,1-diphenylethoxy- magnesium iodide quantitatively. Thus, it has been shown that alkyl- magnesium alkoxides can also be intermediates in the reaction of Grig­ nard compounds with ketones. When inverse addition (e.g. the addition of the Grignard compound to the ketone) was used, employing a 1:1 ratio of reactants the product was again 1,1-diphenylethoxymagnesium iodide. vii The intermediate resulting from the reaction of benzonitrile with methylmagnesium iodide in 1:2 stoichiometry, was isolated and found to be (i), with unreacted Grignard compound again found in the last fraction. 0-C-N=Mg»I«Et2O CH3 A kinetic investigation was attempted in order to determine the mechanism whereby a ketone reacts with a Grignard compound. 2-Methyl- ^-mercaptomethylbenzophenone and methylmagnesium chloride was found to be a satisfactory system for the study. No suitable data was obtained with which to determine the kinetic order of the reaction. A system of analysis was developed, utilizing ultraviolet spectroscopy, with which it was possible to reproduce values for the initial concentration of the ketone to within one per cent. Initial difficulty in preparing stable Grignard solutions at low concentration was overcome. The best method found for preparing Grignard compounds in triethylamine consisted of running the reaction in triethylamine solvent which was previously dis­ tilled from a triethylamine solution of the Grignard compound to be prepared in the reaction. CHAPTER I INTRODUCTION AND HISTORICAL BACKGROUND Grignard reagents have been the subject of much interest and con­ troversy since their discovery in the year 1900^. Since then many at­ tempts have been made to determine the structure and composition of the reagent and to understand the mechanisms by which Grignard compounds react with various classes of organic compounds. A great many contribu­ tions have been made in these areas, particularly in the 1950's and early 1960's, however, many are conflicting and lead to confusion and speculation. It would appear that an exact description of a reaction mechanism is impossible unless the reacting species are known with certainty. Therefore, one must forego consideration of the mechanism whereby a Grignard reagent reacts with an organic functional group until the com­ position of the Grignard compound in solution is well understood. Be­ fore discussing the ultimate objective of this research, which concerns the mechanism of Grignard compound addition to ketones, it is necessary first to consider the nature of the species present in ether solutions of Grignard compounds. Barbier first discovered in 1899 that alkyl halides and ketones react with magnesium metal to produce, on hydrolysis, tertiary alcohols. 1. V. Grignard, Compt. rend., 130, 1322 (1900). 2. P. Barbier, Compt. rend., 128, 110 (1899). 2 Mg H.+ , HO RCOR + CH I * ^> RC(OH)CH3R (l) In 1900 Victor Grignard"'", after whom the reagent is named, dis­ covered that the reaction is actually a two step process involving the formation of an alkylmagnesium halide followed "by subsequent reaction with the ketone, to yield on hydrolysis the tertiary alcohol. Et 0 CH^I + Mg CH^Mgl (2) + H , Ho0 CH^Mgl + RCOR RC(0H)CH3R (3) Although "CH^Mgl" is not the only species in solution, it is most often used to predict the products of the reaction. Several early workers reported on the composition of Grignard 3 compounds in solution. Perhaps the best known is that of Jolibois , who in